Mannose binding lectin gene mutations are associated with progression of liver disease in chronic hepatitis B infection

Abstract

Mannose-binding lectin (MBL) plays an important role in immune defense. We examined the MBL gene mutations and MBL levels in Chinese hepatitis B and hepatitis C patients with and without symptomatic cirrhosis. We recruited 190 hepatitis B and C patients, and 117 normal Chinese as controls. Serum MBL levels were measured by enzyme-linked immunosorbent assay. MBL gene mutation at codons 52, 54, and 57 was detected by polymerase chain reaction (PCR) assay. In asymptomatic hepatitis B and C patients, there was no increase in codons 52, 54, and 57 mutation, but the MBL levels were significantly lower than those in the controls. Codon 54 mutation rate was increased to 44.4% (P ‫؍‬ .007) in symptomatic hepatitis B cirrhosis and 64.3% (P ‫؍‬ .0026) in patients with spontaneous bacterial peritonitis (SBP). There was no increase in codon 54 mutation rate in hepatitis B-related hepatocellular carcinoma (HCC). In chronic hepatitis B infection, the odds ratio for an individual with codon 54 mutation to develop cirrhosis was 1.84 (95% CI: 1.21-2.81) and to develop SBP Mannose-binding lectin (MBL) is a calcium-dependent C-type lectin with a structural analogy to complement component C1q, and plays an important role in host immune defense. It is important in the first line of defense because of its ability to activate the complement system and phagocytosis. [1][2][3][4] Through its collagen domain, it behaves as an opsonin by binding to collectin receptors. 5-7 Low serum MBL leads to an opsonic defect that impairs phagocytosis by polymorphonuclear leukocytes. 8 Previous studies have shown that MBL deficiency may confer a risk of infection in children and adults. 9,10 Point mutation at codons 52 (CGT=TGT), 54 (GGC=GAC), and 57 (GGA=GAA) of the MBL gene are associated with low serum level of MBL and thus immunodeficiency caused by the opsonic defect. 11,12 MBL is synthesized by hepatocytes. 13 Recently, Thomas et al. showed that there was an association between MBL codon 52 mutation and persistent hepatitis B infection in whites. 14 The study did not find an association in the Asian hepatitis B carriers. It is known that the middle surface protein of the hepatitis B virus (HBV) envelope contains high mannose oligosaccharides for the binding of MBL. 15 Therefore, opsonization of the viral particles through MBL binding may be possible. However, whether this is associated with the clearance of serum HBV is not known.Patients with cirrhosis have impaired serum opsonization. 16 Spontaneous bacterial peritonitis (SBP) is a frequent infection that occurs in cirrhotic patients with ascites. It is not known whether there is any relationship between cirrhosis, SBP, and MBL mutation.We studied the serum MBL levels and MBL gene mutations in asymptomatic Chinese hepatitis B carriers, hepatitis C carriers, patients with hepatitis B-related hepatocellular carcinoma (HCC), and patients with hepatitis B-related cirrhosis with or without ascites and SBP. Our aim was to define the possible relationship between MBL levels and its mutations with thes...

Mannose-binding lectin in chronic hepatitis B virus infection

“…27 Although lower serum MBL levels in HBsAg carriers were also observed in the previous study, this could not be entirely explained by increases in the frequency of the B allele. 27 We have demonstrated in the current study that, in addition to allele B, the promoter polymorphism (Ϫ221 X/Y) is associated with the occurrence of the cirrhosis or hepatocellular carcinoma in progressed carriers after controlling for age, sex, ALT ratio to ULN, HBeAg status, HBV DNA titer, and HBV genotype. We further showed that the lower MBL level observed in the progressed carriers when compared with nonprogressed carriers can be explained entirely by the overrepresentation of the low MBL NOTE.…”

“…29 However, in the Chinese allele C and allele D of mbl2 are extremely rare, if not entirely absent. 22,23,27 Another report suggested that allele B (codon 54) was over-represented in Vietnamese patients with acute hepatitis B when compared with healthy controls. 35 However, we did not find any increase in low MBL genotype frequency in spontaneously recovered individuals or nonprogressed HBsAg carriers compared with naïve controls to implicate low MBL levels as a susceptibility factor in acute HBV infection.…”

“…[24][25][26] The other two known mutant haplotypes carrying structural polymorphisms, C (codon 57) and D (codon 52), are at an extremely low frequency and probably absent altogether in the Chinese population. 21,22,27 Several lines of evidence implicate MBL in HBV infection. The preS2 region of the middle hepatitis B surface protein contains a mannose-rich oligosaccharide to which MBL could bind and result in some biological function.…”

“…The preS2 region of the middle hepatitis B surface protein contains a mannose-rich oligosaccharide to which MBL could bind and result in some biological function. 28 Polymorphisms at codon 52 and 54 of mbl2 have been demonstrated to associate with chronic HBV infection in some relatively small scale studies, 27,29 although conflicting negative results were also reported. 30,31 Therefore, the role of MBL in HBV infection and the question of whether the mbl2 SNPs are associated with different outcomes of HBV infection deserve further investigation.…”

Mannose binding lectin (MBL) gene mutation is not a risk factor for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese

“…Previous studies suggest that homozygous deficiency of MBL is associated with recurrent infections in children 3,4 as well as increased susceptibility and shorter survival of human immunodeficiency virus (HIV) patients. 5,6 Although there are controversies, association of MBL deficiency with chronic hepatitis virus type B (HBV) infection 7 and its progression, 8 and with poor response to interferon in chronic hepatitis virus type C (HCV) 9 has also been reported. In addition MBL deficiency has also been implicated in the pathogenesis of autoimmune diseases.…”